Multicenter Randomized Controlled Trial

of Cardiac Contractility Modulation in

Patients with Advanced Heart Failure

William T. Abraham MD, Koonlawee Nademanee MD,

Kent Volosin MD, Steve Krueger MD, Suresh Neelagaru MD,
Nirav Raval MD, Owen Obel MD, Stanley Weiner MD, Mark Wish MD,
Peter Carson MD, Kenneth Ellenbogen MD, Robert Bourge MD,
Mike Parides MD, Richard P Chiacchierini PhD, Rochelle Goldsmith PhD,
Sidney Goldstein MD and Alan Kadish MD on Behalf of the FIX-HF-5
Investigators and Coordinators*

*Dr. Abraham and other members of this group have received consulting fees
and/or research grants from Impulse Dynamics
 Cardiac Contractility Modulation (CCM)
Background

• Preclinical studies have demonstrated that

CCM:
• Increases cardiac contractility
• Reduces myocardial work
• Produces echocardiographic and molecular
changes indicative of ventricular reverse remodeling
• Prior human studies have confirmed these
effects and provided preliminary evidence
supporting the potential clinical benefits of
CCM in patients with systolic heart failure
 The Concept Behind Cardiac Contractility
Modulation (CCM)*
n
a y atio CCM
el ur
D D
Muscle
Amplitude Force

Apply electric signal

during absolute refractory
period

Detect local *This approach to heart failure therapy is

activation investigational.
Optimizer III™ System
 FIX-HF-5 Trial

• Multi-center, unblinded, randomized, parallel-

controlled clinical trial
• 50 participating centers (all US)
• 6-month efficacy endpoint
• 1-year safety endpoint

• First US randomization occurred on April 8,

2005 and the last on June 12, 2007
• Last follow-up completed June 2008
 FIX-HF-5: Study Schematic
Informed Consent

Baseline Testing

Eligibility Determination

Group 1 Group 2

Device Implantation

12 Months
2 week Run-In
Medical
Control

12 Months
CCM 5 hr/day

Study visits at: Baseline, 12Wk, 24Wk and 50Wk

 FIX-HF-5: Study Endpoints
• Primary Efficacy Endpoint: Anaerobic Threshold
(AT) assessed by responders analysis (≥20%
increase in AT = responder)
• Primary Safety Endpoint: Composite of all-cause
mortality and all-cause hospitalization assessed
by non-inferiority analysis (active versus control
group with 12.5% allowable delta)
• Secondary Efficacy Endpoints:
• Peak VO2
• Minnesota Living with Heart Failure Questionnaire
• Other Efficacy Endpoints
• NYHA Functional Class Ranking
• 6-Minute Hall Walk Distance
 Metabolic Exercise Testing and Core Lab
• Single core laboratory where a detailed procedure was
followed for objective determination of AT (using the V-
slope method) by two independent readers blinded to
treatment group
• On-site training on standardized procedures for
conducting metabolic exercise tests and electronic data
transfer to the core laboratory
• Site revalidation every 6 months
• Rapid feedback on test quality from the core laboratory
(on the day the tests were performed)
• Despite these efforts, it was anticipated that substantial
number of tests would be classified as indeterminate,
either because of poor test quality, inability of subjects to
reach AT, or because of poor subject compliance
 Informed Consent
n=774

345 Withdrew or
Ineligible
1 Death Death Prior to
Implant
Randomized n=3
n=428

Control Treatment
n=213 n=215
Not
Failed
Implanted
8 W/D Successful Implant
n=7
1 Death Implant n=2
5 W/D n=203

12Wk 2 W/D
n=204 12Wk 4 Deaths
n=2 12Wk
12Wk
3 W/D Primary n=199
n=2

Efficacy 1 W/D
3 Deaths
24Wk 24Wk
n=201 24Wk
n=2 24Wk
n=2
n=195
6 W/D
6 Deaths
Primary 3 W/D
Safety 3 Deaths

50Wk 50Wk 50Wk 50Wk

n=189 n=2 n=189 n=2
FIX-HF-5: Baseline Characteristics
Control (n=213) Treatment (n=215)
Variable Mean (SD) or n (%) Mean (SD) or n (%) P-value
Age (yrs) 58.55 (12.23) 58.09 (12.79) 0.51091
Male 151 (70.9%) 158 (73.5%) 0.59012
Ethnicity
White 142 (66.7%) 154 (71.6%) 0.50263
Black 45 (21.1%) 36 (16.7%)
Other 26 (12.2%) 25 (11.7%)
Weight (kg) 93.30 (22.16) 91.17 (23.27) 0.16321
BMI (kg/m2) 30.95 (6.53) 30.44 (7.04) 0.21791
Resting HR (bpm) 73.74 (12.19) 73.98 (13.13) 0.96811
SBP (mmHg) 115.61 (17.61) 116.65 (19.48) 0.86951
CHF Etiology
Ischemic 142 (66.7%) 139 (64.7%) 0.64653
Idiopathic 48 (22.5%) 58 (27.0%)
Other 23 (10.8%) 18 (8.3%)
NYHA
Class I 0 (0%) 0 (0%) 0.17203
Class II 1 (0.47%) 0 (0%)
Class III 183 (85.92%) 196 (91.16%)
Class IV 29 (13.62%) 19 (8.84%)
 FIX-HF-5: Baseline Characteristics
Continued
Control (n=213) Treatment (n=215)
Variable Mean (SD) or n (%) Mean (SD) or n (%) P-value
QRS Duration (ms) 101.51 (12.81) 101.63 (15.30) 0.59684
PVCs/24hr (Holter) 1365.1 (2000.9) 1323.3 (1930.6) 0.51131
LVEF (%) 26.09 (6.54) 25.74 (6.60) 0.56411
LVEDD (mm) 63.01 (8.56) 62.41 (9.22) 0.77151
MLWHFQ 57.38 (22.62) 60.49 (23.00) 0.11091
6MW (meters) 323.99 (92.44) 326.38 (82.10) 0.59711
CPX (core lab)
Duration (minutes) 11.50 (3.46) 11.34 (3.20) 0.48141
Peak SBP (mmHg) 138.8 (24.6) 139.7 (27.1) 0.97141
Peak HR (bpm) 121.2 (20.5) 122.1 (20.2) 0.52231
Peak RER 1.13 (0.09) 1.14 (0.10) 0.51891
Peak VO2 (ml/kg/min) 14.71 (2.92) 14.74 (3.06) 0.85751
AT (ml/kg/min) 10.97 (2.18) 10.95 (2.24) 0.97194
 FIX-HF-5: Baseline Medications*

Control Optimizer
Medication n/N (%) n/N (%) P-Value

ACE inhibitor (ACEi) 148/213 (69.48) 153/215 (71.16) 0.7512

Angiotensin receptor blocker (ARB) 51/213 (23.94) 52/215 (24.19) 1.0000
ACEi or ARB 195/213 (91.55) 195/215 (90.70) 0.8654
Beta Blocker 198/213 (92.96) 202/215 (93.95) 0.7005
Loop Diuretic 194/213 (91.08) 198/215 (92.09) 0.7307
Second Diuretic 12/210 (5.71) 19/212 (8.96) 0.2629
Aldosterone Inhibitor 102/213 (47.89) 95/215 (44.19) 0.4973
Hydralazine 15/213 (7.04) 12/215 (5.58) 0.5574
Nitrates 75/213 (35.21) 73/215 (33.95) 0.8391
Calcium Channel Blocker 9/213 (4.23) 18/215 (8.37) 0.1103
Anti -arrhythmic 28/213 (13.15) 37/215 (17.21) 0.2816

*95% of all subjects also had an implantable cardioverter defibrillator

 Primary Safety Endpoint
All-Cause Mortality Plus All-Cause Hospitalizations

• Control Group:
• 103 events in 213 subjects = 48%
• CCM Group:
• 112 events in 215 subjects = 52%
• Statistical tests confirm that the safety
endpoint was met:
• Blackwelder test of noninferiority: p=0.034
• Log-Rank test: p=0.22
 Primary Efficacy Endpoint
Anaerobic Threshold Responder Analysis

• Completors analysis:
• Control: 18/154 (11.7%)
• Treatment: 28/159 (17.6%)
• Difference: 5.9% (P = 0.093)

• Intention-to-Treat analysis*:
• Control: 28/213 (13.2%)
• Treatment: 38/215 (17.7%)
• Difference: 4.5% (P = 0.314)

*27% missing data requiring imputation per analysis plan

 Primary Efficacy Endpoint
Anaerobic Threshold Comparison of Mean Change

0.1
∆ Anaerobic Threshold

Control Treatment Difference

0.0
p=ns
(ml/kg/min)

-0.1

-0.2

-0.3
 Secondary Efficacy Endpoint
Peak VO2 Comparison of Mean Change

0.75 p=0.024

0.50

0.25
(ml/kg/min)
∆ Peak VO 2

Control
0.00
Treatment Difference
-0.25

-0.50
-0.75
 Secondary Efficacy Endpoint
Quality of Life Comparison of Mean Change

Control Treatment Difference

0

-5
∆ MLWHFQ

-10
p<0.0001

-15

-20
 Other Efficacy Endpoint
Change in NYHA Functional Class

50

40
(% Patients with ≥ 1
Point Reduction)

30
NYHA

20 p=0.0026

10

0
Control Treatment Difference
 Other Efficacy Endpoint
6-Minute Hall Walk Distance Comparison of
Mean Change
30
Six Minute Walk (m)

20

p=0.108
10

0
Control Treatment Difference
 SUBGROUP ANALYSES*

∆VAT
N (ml/kg/min) p
EF<25 205 -0.59 0.09
EF≥25 223 0.53 0.15
NYHA III 380 0.13 0.55
NYHA IV 48 -1.21 0.10
NYHA III + EF≥25 200 0.69 0.04
NYHA IV + EF<25 25 -1.17 0.19

*Hypothesis Generating
 Subgroup Analysis:
Baseline EF ≥ 25 and NYHA III
Responders Analysis

Control Treatment Treatment-

Parameter (n=84) (n=101) Control P*
VAT (ml/kg/min) 4/69(5.8%) 17/83(20.5%) 14.7% 0.0073
VAT (ml/kg/min) (ITT) 9/97 (9.4%) 23/109 (21.5%) 12.1 0.023
Peak VO2 (ml/kg/min) 3/76(3.95%) 18/94(19.15%) 15.2% 0.002
MLWHFQ 35/84(41.7%) 60/101(59.4%) 17.7% 0.0119
NYHA Class 19/82(23.2%) 43/97(44.3%) 21.1% 0.0023
6MW (meters) 20/79 (25.3) 36/97 (37.1) 11.8% 0.065
ITT, intention to treat population
*P values by one-sided Fisher's exact test
 Subgroup Analysis:
Baseline EF ≥ 25 and NYHA III
Comparison of Changes in Mean Values

Control Treatment Treatment-

Parameter (n=84) (n=101) Control P*
VAT ml/kg/min) -0.54±1.83 0.10±2.36 0.64 0.024
Peak VO2 -0.97±2.31 0.34±3.11 1.31 0.001
MLWHFQ -6.0±21.9 -16.8±20.2 -10.8 0.0003
NYHA Class -0.17±0.64 -0.46±0.61 -0.29 0.0011
6MW 0.8 (82.6) 21.5 (77.5) 20.7 0.0445
*P values by one-sided equal varance Student's t-test
 Potential Study Limitations

• Choice of anaerobic threshold as a

primary endpoint
• Missing VAT data despite rigorous
approach to metabolic exercise testing
• Use of responders analyses
• Un-implanted control group (no
blinding)
 FIX-HF-5: Summary
• CCM failed to improve the anaerobic threshold,
pre-specified as the primary endpoint of the trial
• In the overall population, CCM significantly
improved
• Peak VO2
• Quality of Life (MLWHFQ score)
• NYHA
• In a subgroup comprising ~50% of study
population (EF≥25, NYHA III), CCM significantly
improved
• Peak VO2
• AT
• MLWHFQ
• NYHA
 Study Oversight Committees

• Executive Steering Committee

• William Abraham, Alan Kadish, Kenneth Ellenbogen,
Robert Bourge, Koonlawee Nademanee, Michael
Parides
• Data Safety Monitoring Board
• Sidney Goldstein, Steven Gottlieb, Andrea Natale,
David Callans, David Naftel
• Events Adjudication Committee
• Peter Carson, Inder Anand, Christopher O’Conner
 Study Principal Investigators
Suresh Neelagaru, Amarillo, TX
Andrew Merliss, Lincoln, NE
Stanislav Weiner, Tyler, TX
Jose Joglar, Dallas, TX
Nirav Raval, Atlanta, GA
Koonlawee Nadamanee, Inglewood, CA
Masood Akhtar, Milwaukee, WI
Kent Volosin, Philadelphia, PA
Freddy Abi-Samra, New Orleans, LA
Marc Wish, Fairfax, VA
Imran Niazi, Milwaukee, WI
Gervasio Lamas, Miami, FL
Javier Sanchez, Austin, TX
Eli Gang, Beverly Hills, CA
Davis Baran, Newark, NJ
Randy Lieberman, Detroit, MI
Alan Bank, St. Paul, MN
Jeffrey Goldberger, Chicago, IL
Allan Murphy, Newport, VA
Jonathan Langberg, Atlanta, GA
Charles Love, Columbus, OH
Frank McGrew III, Germantown, TN
Hue-The Shih, Houston, TX
Seth Worley, Lancaster, PA
Roy John, Burlington, MA
Davis Smull, Winston-Salem, NC
Raffaele Corbisiero, Trenton, NJ
Steven Greenberg, Roslyn, NY
Mari Rosa Costanzo, Naperville, IL
Thomas Mattioni, Scottsdale, AZ
Steven Hao, Larkspur, CA
Mark Wathen, Nashville, TN
David Hayes, Rochester, MN
Andrew Cohen, Aurora, CO
Bengt Herweg, Tampa, FL
Harold Goldberg, Spokane, WA
Jill Kalman, New York, NY
Gregory Jones, Kingsport, TN
Nancy Sweitzer, Madison, WI
Mark Wood, Richmond, VA
Jonathan Steinberg, New York, NY
Jose Tallaj, Birmingham, AL
Alan Heywood, Bellevue, WA
Barbara Czerska, Detroit, MI
Gregory Buser, Larkspur, CA
Steven Klein, Greensboro, NC